Group A Streptococcus: another resistant pathogen.

Objectives: In Greenville, South Carolina in 1992, erythromycin resistance in GAS was less than 5%, and there were no fully resistant strains. With a large increase in macrolide and azalide usage within the Greenville area, we again examined susceptibility patterns of pharyngeal GAS isolates in 2002 to 2003.

Methods: Community pediatric offices supplied 106 GAS isolates for study. Screening for macrolide resistance was done via Kirby-Bauer disk diffusion testing. Zones of inhibition from 16 to 20 mm were interpreted as intermediately resistant, and those 15 mm or less were interpreted as resistant per National Committee for Clinical Laboratory Standards guidelines.

Results: A total of 106 GAS isolates were tested; 0.9% of isolates were intermediately resistant to erythromycin and 11% were fully resistant.

Conclusions: The rate of erythromycin resistance among GAS isolates has increased in the past 10 years in the Greenville community. This pattern has paralleled the increased utilization of macrolides in the same community. Continued monitoring of resistance rates will be needed to alert practitioners of possible treatment failures due to macrolide resistance.

Key Words: Group A Streptococcus, macrolide resistance, azalide resistance

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Erythromycin resistance in Group A Streptococcus (GAS) has increased in prevalence over the past several years. A study done in Greenville, South Carolina from pediatric isolates of GAS demonstrated an increase in isolates resistant to erythromycin. This appears to correlate with increased azalide usage in the same community. This suggests that erythromycin usage may not be the only indicator to predict macrolide resistance patterns in GAS.

Group A Streptococcus continues to be the most common bacterial etiology of pharyngitis in children. In addition to being a prevalent pathogen in sore throats, GAS is also responsible for sequelae such as rheumatic fever and post-streptococcal glomerulonephritis. Penicillin remains the standard treatment, although cephalosporins are becoming a reasonable alternative given reports of penicillin failures. (1) Macrolides are recommended for use in people with penicillin allergies. (2) With the availability of once-daily dosing and five-day regimens, (3) newer azalides such as azithromycin have become increasingly popular in the treatment of bacterial pharyngitis in penicillin-allergic and nonallergic patients.

This growing trend of macrolide-resistant GAS has been documented in other areas of the world as well. European and Asian countries, including Finland, Italy, England, Greece, Taiwan, and Japan, have also witnessed this phenomenon. (2,4) These countries have shown that there is a correlation between the increased resistance pattern of GAS to macrolides and the increased use of this class of antibiotics. (5) In 2002, researchers at the University of Pittsburgh described a clonal outbreak of erythromycin-resistant GAS pharyngeal isolates. (6) This data further documented that erythromycin-resistant GAS is an emerging pathogen in the United States. Research in 1992 revealed that less than 5% of 187 GAS isolates from pediatric offices in Greenville, South Carolina had erythromycin resistance. These isolates were classified as intermediately resistant, and at the time, there were no fully resistant strains. Within the Greenville area, a study was conducted to examine susceptibility patterns of pharyngeal GAS isolates in the winter of 2002 to 2003. The purpose was to determine if data from our community, which experienced a large increase in azalide and macrolide use, paralleled that described in other US studies.

Methods

Community pediatric offices and local emergency rooms supplied 106 GAS isolates for the study. These were collected weekly and taken to the microbiology lab at Greenville Memorial Hospital. Each isolate was numbered and then purified. Bacitracin disks were used to confirm GAS. They were screened for macrolide resistance via Kirby-Bauer disk diffusion testing. E-tests were used to determine minimal inhibitory concentrations (MICs) in all strains found on screening to be resistant and intermediately resistant. Both Kirby-Bauer and E-test methods were quality controlled using the National Committee for Clinical Laboratory Standards (NCCLS).

Data and Results

Out of 106 isolates collected, we found 12 isolates to be fully resistant and one isolate to be intermediately resistant to erythromycin. Six of these isolates had an MIC of greater than 256. Other MICs were as follows: one isolate with an MIC of 32, one isolate with an MIC of 24, three isolates with an MIC of 16, and one isolate with an MIC of 1.5. The one intermediately resistant isolate had an MIC of 0.5. (Table) These MICs reflect 11% macrolide resistance and 0.9% intermediate resistance among the GAS isolates tested. An analysis of changes in resistance was done. Comparison of resistance rates in 1992 and 2002 demonstrated a statistically significant relative risk of 2.55 (1.13; 5.76) with a P = 0.036.

Discussion

Erythromycin resistance among GAS isolates has increased in the past ten years in the Greenville area. It is hypothesized that this increase parallels increased macrolide and azalide usage in the same community. This correlation has been well described in the literature. In Finland and Japan, the increased resistance of GAS to erythromycin paralleled the increased use of the macrolide class. Conversely, a decreased rate of erythromycin resistance in these countries was seen when the rate of erythromycin use decreased, due to a physician education program. A decrease in the incidence of resistant GAS was noted to directly correlate with the decreased use of macrolides as first-line agents. (7-9)

The two most common mechanisms of erythromycin resistance include an active efflux of erythromycin from the cell and target site modification. (2) The majority of resistance is attributed to two genes, mefA and erm. The mefA gene produces a membrane protein which participates in the efflux. It specifically targets 14- and 15-member macrolides. Erm genes permanently alter ribosomes causing an inability of the macrolides to bind, thus inhibiting the drug's action. We hypothesize that erm genes elicit permanent resistance, and therefore our isolates (46%) that exhibit MICs greater than 256 contain this gene.

Interventions to decrease the rates of macrolide resistance in a community might include education of physicians in the proper diagnosis of streptococcal pharyngitis and the use of [beta]-lactams as first-line therapy for GAS in nonpenicillin-allergic patients. In the Greenville community, approximately 30% of antibiotics prescribed during the time these GAS isolates were collected were for azithromycin. Azithromycin was not available in pediatrics until 1995. The original group of GAS isolates was collected before the availability of azalides for children. This supports the hypothesis that as the rate of azithromycin use increases, so does the rate of erythromycin resistance to GAS. Monitoring of erythromycin resistance in GAS isolates will assist physicians in therapeutic decisions regarding treatment of GAS and hopefully alert physicians to be diligent in using [beta]-lactams as first-line therapy in nonpenicillin-allergic patients.

Acknowledgments

We would like to thank Dean Benjamin, MT, Supervisor of Microbiology, for her assistance with conduction of this research.

References

1. Casey JR, Pichichero ME. Meta-analysis of cephalosporin versus penicillin treatment of Group A streptococcal tonsillopharyngitis in children. Pediatrics 2004;113:866-882.

2. Syrogiannopopoulos GA, Grivea IN, Fitoussi F, et al. High prevalence of erythromycin resistance of Streptococcus pyogenes in Greek children. Pediatr Infect Dis J 2001;20:863-868.

3. Seppala H, Nissinen A, Jarvinen H, et al. Resistance to erythromycin in Group A streptococci. N Engl J Med 1992;326:292-297.

4. De Azavedo JC, Yeung RH, Bast DJ, et al. Prevalence and mechanisms of macrolide resistance in clinical isolates of Group A streptococci from Ontario, Canada. Antimicrob Agents Chemother 1999;43:2144-2147.

5. Cizman M, Pokorn M, Seme K, et al. The relationship between trends in macrolide use and resistance to macrolides of common respiratory pathogens. J Antimicrob Chemother 2001;47:475-477.

6. Martin JM, Green M, Barbadora KA, et al. Erythromycin-resistant group A streptococci in school children in Pittsburgh. N Engl J Med 2002;346:1200-1206.

7. Fujita K, Murono K, Yoshikawa M, et al. Decline of erythromycin resistance of Group A streptococci in Japan. Pediatr Infect Dis J 1994;13:1075-1078.

8. Seppala H, Klaukka T, Lehtonin R, et al. Outpatient use of erythromycin: link to increased erythromycin resistance in Group A streptococci. Clin Infect Dis 1995;21:1378-1385.

9. Seppala H, Klaukka T, Vuopio-Varkila J, et al. The effects of changes in the consumption of macrolide antibiotics on erythromycin resistance in Group A streptococci in Finland: a Finnish study group for antimicrobial resistance. N Engl J Med 1997;337:441-446.

Robin LaCroix, MD, and Anna Kathryn Rye, MD

From Greenville Hospital System, University Medical Group, Children's Hospital, Greenville, SC 29615. Email: [e-mail]

Reprint requests to Dr. Robin LaCroix, Pediatric Infectious Disease, 200 Patewood Drive, Suite A200, Greenville, SC 29615.

Supported by The Children's Hospital, of the Greenville Hospital System University Medical Group.

Accepted August 28, 2006.

RELATED ARTICLE: Key Points

* Streptococcus pyogenes has increasing resistance to macrolides.

* Use of azalides and macrolides may be a factor in increasing resistance.

* Geographic variations of Streptococcus pyogenes resistance have been well described in the medical literature.

Table. E-Test results

MIC (mcg/mL)  No. of isolates

256           6
 32           1
 24           1
 16           3
  1.5         1
  0.5         1

MIC, minimal inhibitory concentration.